2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure Data Supplement

(Section numbers correspond to the 2013 full-text guideline.)

Table of Contents Data Supplement 1. RCTs Comparing ARNI (Section 7.3.2.10) ...... 1 Data Supplement 2. RCTs Comparing RAAS Inhibition (Section 7.3.2.3) ...... 3 Data Supplement 3. RCTs Comparing Pharmacological Treatment for of ARNI With ACE (Section 7.3.2.10)...... 5 Data Supplement 4. RCTs Comparing Pharmacological Treatment for Stage C HFrEF (Section 7.3.2.11) ...... 7 2013 HF Guideline Data Supplement 18. ACE Inhibitors (Section 7.3.2.2) ...... 10 2013 HF Guideline Data Supplement 19. ARBs (Section 7.3.2.3)...... 13 2013 HF Guideline Data Supplement 20. Beta Blockers (Section 7.3.2.4) ...... 14 References ...... 17

Data Supplement 1. RCTs Comparing ARNI (Section 7.3.2.10) Study Acronym; Aim of Study; Patient Population Study Intervention Endpoint Results Relevant 2° Endpoint (if any); Author; Study Type; (# patients) / (Absolute Event Rates, Study Limitations; Year Published Study Size (N) Study Comparator P values; OR or RR; & Adverse Events (# patients) 95% CI) PARAMOUNT Aim: Inclusion criteria: Intervention: 1° endpoint: • No difference in change in NT-proBNP Solomon et al. 2012 To address safety Pts ≥40 y of age, LVEF ≥45%, NYHA LCZ696 (149) target dose • Change from BL at 12 wk from BL at 36 wk (1) and efficacy of class II-III HF, NT-pro BNP >400 200 mg BID achieved in for NT-proBNP • BP reduced in the LCZ696 group vs. 22932717 LCZ696 (ARNI) in pg/mL. 81% • Results: Reduction in valsartan at 12 wk (p=0.001 for SBP and pts with HFpEF LCZ696 group vs. p=0.09 for DBP) Exclusion criteria: valsartan (ratio of change • Change in BP correlated poorly with the Study type: Right HF due to pulmonary disease, Comparator: from BL: 0.77, 95% CI: change in pro-BNP RCT dyspnea due to noncardiac causes, Valsartan (152) target 0.64–0.92; p=0.005) • No difference in improvement in NYHA valvular/myocardial disease, CAD dose 160 mg BID class at 12 wk (p=0.11) and 36 wk Size: or CVD needing revascularization achieved in 78% 1° Safety endpoint: (p=0.05). 308 within 3 mo of screening. • LCZ-696 well tolerated. • No difference in KCCQ scores • Serious adverse events: • Trial not powered to ascertain clinical 1 © 2016 American College of Cardiology Foundation and American Heart Association, Inc.

15% in LCZ696 vs. 20% in outcomes. Further studies needed to valsartan group assess safety and efficacy in HFpEF pts. PARADIGM-HF Aim: Inclusion criteria: Intervention: 1° endpoint: • Less CV death in LCZ696 arm (558 vs. McMurray et al. To compare survival ≥18 y of age, NYHA class II, III, IV; LCZ696 (4,187) target • Composite of death (CV 693) HR: 0.8 (95% CI: 0.71–0.89; 2014 rates with the use of EF ≤35%, BNP of at least 150 dose 200 mg BID (mean causes) or a first p<0.001) (2) LCZ696 with pg/mL, hospitalized for HF <12 mo 375+71 mg daily) hospitalization for HF • Less HF hospitalizations in LCZ696 arm 25176015 enalapril in HF (≥BNP100 pg/mL), on ACE (537 vs. 658) HR: 0.79 (95% CI: 0.71– inhibitors or ARBs ≥4 wk before Comparator: • Results: Composite less in 0.89; p<0.001) Study type: screening, required to take stable Enalapril (4,212) target 10 LCZ696 group vs. • Less death from any cause in LCZ696 RCT dose of beta blockers and an ACE mg BID (mean 18.9+3.4 enalapril, 914 (21.8%) vs. arm (711 vs. 835), HR: 0.84 (95% CI: inhibitor (or ARB) equal to 10mg of mg daily) 1,117, (26.5%) HR: 0.80 0.76–0.93; p<0.001) Size: enalapril. Prior to randomization pts (95% CI: 0.73–0.87; • The change from baseline to 8 mo in the 8,442 were required to complete 2 wk p<0.001) score on the KCCQ in LCZ696 arm (2.99 each of enalapril 10 mg BID and points reduction vs. 4.63 points), HR: LCZ 100 BID. 1.64 (95% CI: 0.63–2.65; p=0.001) • No difference in new onset of AF (84 vs. Exclusion criteria: 83; p=0.84) Symptomatic hypotension, SBP <95 • No difference in protocol defined decline mm Hg, eGFR <30 2 in renal function, HR: 0.86 (95% CI: mL/min/min/1.73m of body surface 0.65–1.13; p=0.28). area, serum K level >5.2 mmol/L, • More symptomatic hypotension (14% vs. angioedema history, unacceptable 9.2%; p<0.001) side effects of ACE inhibitors or • No difference in angioedema, 19 vs.10 ARBs (p=0.13) AF indicates atrial fibrillation; ARNI/LCZ696, angiotensin receptor-neprilysin inhibitor; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BL, baseline; BID; twice a day; BNP, plasma B-type natriuretic peptide; BP, blood pressure; CAD, coronary artery disease; CI, confidence interval; CVD, cardiovascular disease; CV, cardiovascular; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HR, hazard ratio; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; N/A, not available; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PARAMOUNT, Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction; PARADIGM-HF, Prospective Comparison of ARNI With ACE to Determine Impact on Global Mortality and Morbidity in Heart Failure; pts, patients; RCT, randomized controlled trial; and SBP, systolic blood pressure. Search Terms and Date: 3 trials identified by chairs in December 2015.

Data Supplement 2. RCTs Comparing RAAS Inhibition (Section 7.3.2.3) Study Acronym; Aim of Study; Patient Population Study Intervention Endpoint Results Relevant 2° Endpoint (if any); Author; Study Type; (# patients) / (Absolute Event Rates, Study Limitations; Year Published Study Size (N) Study Comparator P values; OR or RR; & Adverse Events (# patients) 95% CI) ONTARGET Aim: Compare ACE Inclusion Criteria: Pts >55 y Intervention: Runin, then 1° endpoint: • Compared to the ramipril arm: ONTARGET (ramipril), ARB of age, CAD, PVD, previous randomization to ramipril • Composite of CV death, MI, stroke, or • Telmisartan had more Investigators et al. (telmisartan), and stroke, or high-risk DM with (8,576) target dose 10 HF hospitalization at 5 y hypotensive symptoms 2008 combination end-organ damage mg daily, telmisartan (p<0.001); less cough (p<0.001) (3) ACE/ARB in pts (8,542) target dose 80 Results: No difference in outcome and angioedema (p=0.01); same 18378520 with CVD or high- Exclusion Criteria: HF at trial mg daily or combination (16.5% ACE, 16.7% ARB, 16.3% syncope. risk DM entry, ACE or ARB (8,502), titrated to BP combination; CI: ARB RR: 1.01 (95% CI: • Combination arm had more intolerance, 0.94–1.09) hypotensive symptoms Study Type: RCT revascularization planned or (p<0.001); syncope (p=0.03); and <3 mo renal dysfunction (p<0.001) Size: 25,620 • BP fell by 6.4/7.4/9.8 mm Hg • Less angioedema with telmisartan TRANSCEND Aim: To assess the Inclusion Criteria: ACE- Intervention: Run in, then 1° endpoint: • No difference in 2° outcomes; Yusuf et al. 2008 effectiveness of intolerant pts with CAD, randomization to • Composite of CV death, MI, stroke, or ARB was safe in this pt (4) ARB in ACE- PVD, previous stroke, or telmisartan titrated to 80 HF hospitalization at 5 y population - no angioedema 18757085 intolerant pts with high-risk DM with end-organ mg as tolerated (2,954) CVD or high-risk damage Results: No significant difference RR: DM Comparator: Titration of 0.92 (95% CI: 0.81–1.05); p=0.216 Exclusion Criteria: HF at trial other mediations as Study Type: RCT entry, revascularization needed to control BP planned or <3 mo (2,944) Size: 5,926 SUPPORT Aim: Discover Inclusion Criteria: Pts 20– Intervention: 1° endpoint: • Pts on triple therapy with Sakata et al. 2015 whether addition of 79 y of age with Randomization to • Composite of all-cause death, MI, ACE/ARB/Beta blocker had more (5) ARB to ACE and hypertension, NYHA class olmesartan (578) titrated stroke, or HF hospitalization at 4.4 y of 1° composite outcome, 38.1 vs. 25637937 beta blockers in II-IV, stable on ACE ± beta up to 40 mg as tolerated 28.2%, HR: 1.47 (95% CI: 1.11– pts with chronic HF blockers (578) (mean dose Results: No significant difference RR: 1.95; p=0.006); all-cause death, will improve clinical achieved at 5 y, 17.9 1.18 (95% CI: 0.96–1.46); p=0.11 19.4 vs. 13.5%, HR: 1.50 (95% CI: outcomes Exclusion Criteria: mg/d) 1.01–2.23; p=0.046); and renal Creatinine >3.0, MI or, dysfunction (21.1 vs. 12.5%, HR: Study Type: Open revascularization within 6 Comparator: Titration to 1.85 (95% CI: 1.24–2.76; p=0.003). label blinded mo control BP without use endpoint of an ARB (568)

EMPHASIS subgroup Aim: Investigate the Inclusion Criteria: Pts Intervention: 1° endpoint: • The beneficial effects of analysis safety and efficacy enrolled in EMPHASIS at high Randomization to • Efficacy: Hospitalization for HF or eplerenone were maintained in Eschalier et al. 2013 of eplerenone in risk for hyperkalemia of eplerenone worsening renal failure. Safety: K >5.5, the high-risk subgroups. (6) pts at high risk for worsening renal function (>75 >6.0, <3.5, hospitalization for significant 23810881 hyperkalemia y, DM, eGFR <60, or SBP Comparator: Placebo hyperkalemia, hospitalization for <123) worsening renal function Study Type: Prespecified Exclusion Criteria: eGFR<30 Results: Efficacy: reduced composite subgroup analysis endpoint. Safety: increased risk of K+ of RCT >5.5 mmol/L, hospitalization for hyperkalemia or discontinuation of Size: 2,737 study medication due to adverse events. No differences from the main trial results in the high-risk subgroups. K >5.5 was increased in the whole cohort and the subgroups, but K >6.0, clinically significant hyperkalemia, and change in eGFR were not substantially higher. RALES Aim: Inclusion Criteria: Intervention: 1° endpoint: • Reduction in death from cardiac Pitt et al. 1999 To investigate the NYHA class III, IV; HF≤6 mo, Spironolactone 25 mg daily • Death from all causes causes and Hospitalization for (7) effect of Left EF≤35%, On ACE (822) cardiac causes (p<0.001) 10471456 spironolactone on inhibitors, loop diuretic. Results: • Improvement in NYHA class mortality and Digitalis and vasodilators Comparator: • Placebo vs. Spironolactone group (46% (p<0.001) morbidity in pts allowed. Placebo (841) vs. 35%; RR: 0.70; 95% CI: 0.60–0.82; • No clinically important safety with severe HF. p<0.001) concerns for electrolytes. Exclusion Criteria: • Trial stopped early due to favorable Gynecomastia/breast pain more Study Type: 1° operable VHD (other than results at 24 mo. frequent in the spironolactone RCT mitral or tricuspid), ACHD, group (p<0.001) unstable angina, 1° heaptic Size: failure, active cancer, life 1,663 threatening disease, heart transplant, serum Cr ≥2.5 mg/dL, serum K ≥5.0 mmoL/L 1° indicates primary; 2°, secondary; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blockers; ACHD, adult congenital heart disease; BP, blood pressure; CAD, coronary artery disease; CI, confidence interval; CVD, cardiovasculardisease; CV, cardiovascular; DM, diabetes mellitus, eGFR, estimated glomerular filtration rate; EMPHASIS, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; HF, heart failure; MI, myocardial infarction; NNH, number needed to harm; NYHA, New York Heart Association; ONTARGET, The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial; pts, patients; PVD, peripheral vascular disease; RCT, randomized controlled trial; RR, relative risk; SBP, systolic blood pressure; SUPPORT, Supplemental Benefit of ARB in Hypertensive Patients With Stable Heart Failure Using Olmesartan; TRANSCEND, the Telmisartan Randomised Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease; and VHD, valvular heart disease. Search Terms and Date: angiotensin-receptor blockers, ARBs, angiotensin-receptor blocker, ARB, angiotensin-receptor antagonists, angiotensin receptor antagonist, candesartan, irbesartan, losartan, telmisartan, valsartan, olmesartan, AND heart failure or congestive heart failure or CHF or HFrEF AND clinical trial, January 2016.

The ARB evidence table from the 2013 Heart Failure Guideline is included at the end of this document.

The ACE inhibitor evidence table from the 2013 Heart Failure Guideline is also included at the end of this document.

The Beta Blocker evidence table from the 2013 Heart Failure Guideline is included at the end of this document.

Data Supplement 3. RCTs Comparing Pharmacological Treatment for of ARNI With ACE (Section 7.3.2.10) Study Acronym; Aim of Study; Patient Population Study Intervention Endpoint Results Relevant 2° Endpoint; Author; Study Type; (# patients) / (Absolute Event Rates, Study Limitations; Year Published Study Size (N) Study Comparator P values; OR or RR; & Adverse Events (# patients) 95% CI) IMPRESS Aim: Determine if Inclusion criteria: Intervention: 1° endpoint: Change in 2° endpoint: Rouleau et al. inhibition of neutral • Informed consent Omapatrilat (289) target exercise duration from • No difference in combined 2000 endopeptidase and • Age ≥18 dose 40 mg daily baseline to wk 12 endpoint of death and admission for (8) ACE with the • Stable (>3 mo) symptomatic HF (NYHA class worsening HF (p=0.52) 10968433 vasopeptidase II–IV HF) Comparator: Lisinopril Results: • Combined endpoint of death and inhibitor omapatrilat • Decreased LVEF <40 (284) target dose 20 mg Similar exercise duration comorbidity for worsening HF was is better than ACE • ≥4 wk dose of ACE inhibitors daily at 12 wk (p=0.45) better for omapatrilat HR: 0.52 (95% inhibition alone with • Seated SBP ≥90 mm Hg CI: 0.28–0.96; p=0.035) lisinopril • Angioedema occurred in no pts Exclusion criteria: taking omapatrilat vs. 1 taking Study type: Double • Uncontrolled hypertension enalapril blind RCT • Acute coronary events within 3 mo

• Comments: Vasopeptidase inhibitor Size: 573 pts Revascularization within 3 mo • Serum potassium <3.5 or >5.3 mmol/L omapatrilat did not improve exercise tolerance compared with ACE • Creatinine >221 mcmol/L inhibitor lisinopril • Transaminases >2 upper limit of normal • Leucocytes <3.0x109/L, neutrophils <1. 5x109/L, or platelets <120x109/L • Use of beta blockers <6 mo • Calcium channel blockers for use other than AF • Pts included in previous RCTs of omapatrilat OVERTURE Aim: Determine dual Inclusion criteria: Intervention: 1° endpoint: Combined • Omapatrilat reduced risk of death Packer et al. 2002 ACE and NEP • NYHA class II–IV HF due to non/ischemic Omapatrilat (2,886), risk of death or and hospitalization for chronic HF (9) inhibitors provides cardiomyopathy for ≥2 mo, or target dose 40 mg daily hospitalization for HF HR: 0.89 (95% CI: 0.82–0.98; 12186794 greater benefit in pts • LVEF ≤30% and hospitalized for HF within 12 achieved 82.5% requiring IV treatment p=0.012). For this analysis, pts were with HF than ACE mo treated with intensification of oral inhibitors alone Comparator: Enalapril Results: No significant medications. Exclusion criteria: (2,884) target dose 10 difference HR: 0.94 (95% 5 © 2016 American College of Cardiology Foundation and American Heart Association, Inc.

Study type: Double • Surgically correctable or reversible cause of mg BID achieved 86.4% CI: 0.86–1.03; p=0.187) • More frequent angioedema with blind RCT HF omapatrilat (0.8% vs. 0.5%) • Likely to receive cardiac transplant or left Size: 5,770 pts ventricular assist device • Severe 1° pulmonary, renal, or hepatic disease • Hx of intolerance to ACE inhibitors • ACS within 1 mo • Coronary revascularization or an acute cerebral ischemic event within 3 mo • Hx of ventricular tachycardia, ventricular fibrillation, or sudden death who did not have an implantable cardioverter-defibrillation placed and had not fired within 2 mo • Hx or hospitalization or intravenous therapy for HF within 48 h • Intravenous positive inotropic agent within 2 wk • SBP >180 or <90 mm Hg • Heart rate >130 bpm • Serum creatinine >2.5 mg/dL • Serum potassium <3.5 or >5.2 mmol/L OCTAVE Aim: Compare safety Inclusion criteria: Intervention: 1° endpoints: 2° endpoints: Kostis et al. 2004 and efficacy of dual • Age ≥18 Omapatrilat target dose • Reduction in SBP at wk • Reduction in DBP at wk 8 (10) ACE and NEP • 3 separate BP criteria for 3 groups: Group 1 80 mg daily 8 • Reduction in SBP and DBP at wk 14751650 inhibitors to ACE untreated hypertension (SBP ≥140 mm Hg or • Need for new 24 inhibitors alone DBP ≥90 mm Hg); Group 2 hypertension and Comparator: Enalapril adjunctive • BP control (SBP <140 mm Hg and persistent mild hypertension (trough SBP 140– target dose 40 mg daily antihypertensive therapy DBP <90 mm Hg) at wk 8 and 24 Study type: Double 159 mm Hg and DBP <100 mm Hg, or trough by wk 24 blind RCT DBP 90–99 mm Hg and SBP <160 mm Hg); Comments: Group 3 hypertension with persistent moderate • Greater reductions in BP in Size: 25,302 pts to severe hypertension (trough SBP 160–179 omapatrilat within each study mm Hg and DBP <110 mm Hg, or trough DBP (p<0.001) 100–109 mm Hg and SBP <180 mm Hg) • Overall mean reduction in SBP ≥3.6 mm Hg Exclusion criteria: • Larger reductions in BP in black • Contraindication to therapy with ACE inhibitors pts with omapatrilat than with or angiotensin II receptor antagonists enalapril. But overall reduction • Hx of angioedema, anaphylaxis, drug-induced smaller with both drugs than in other or chronic urticarial, or multiple drug sensitivities subgroups. • Recent hospitalization for MI, unstable angina, • Adverse events, serious adverse stroke, TIA or COPD events, and deaths were the same • Recent treatment for malignancy, chronic renal for omapatrilat and enalapril 6 © 2016 American College of Cardiology Foundation and American Heart Association, Inc.

disease 2° to autoimmune disease, or end-stage • More angioedema with omapatrilat renal disease of any etiology (2.17% vs. 0.68%) • Hypertensive pts treated with ACE inhibitors • More angioedema in blacks with whose BP placed them in study group 3 omapatrilat (5.54% vs. 1.62%) and current smokers (3.93% vs. 0.81%) 1° indicates primary; 2°, secondary; ACE, angiotensin converting enzyme; ACS, acute coronary syndrome; BP, blood pressure; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DPB, diastolic blood pressure; HF, heart failure; Hx, history; IV, intravenous; IMPRESS, Comparison of Vasopeptidase Inhibitor, Omapatrilat, and Lisinopril on Exercise Tolerance and Morbidity; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; NEP, neutral endopeptidase; OVERTURE, Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events; OCTAVE, The Omapatrilat Cardiovascular Treatment vs. Enalapril; pts, patients, RCT, randomized controlled trial; RR, relative risk; SBP, systolic blood pressure; TIA, transient ischemic attack. Search Terms and Date: March 2016, angioedema, neprilysin inhibitors, omapatrilat.

Data Supplement 4. RCTs Comparing Pharmacological Treatment for Stage C HFrEF (Section 7.3.2.11) Study Acronym; Aim of Study; Patient Population Study Intervention Endpoint Results Relevant 2° Endpoint (if any); Author; Study Type; (# patients) / (Absolute Event Rates, Study Limitations; Year Published Study Size (N) Study Comparator P values; OR or RR; & Adverse Events (# patients) 95% CI) SHIFT HF Aim: Inclusion criteria: Intervention: 1° endpoint: • Number of comorbidities was related to outcomes Böhm et al. 2015 To assess influence Pts ≥18 y of age in sinus Ivabradine • Heart rate reduction with Ivabradine is conserved at (11) of comorbidities rhythm, heart rate at rest • CV death or HF all comorbidity loads 26508709 on outcomes and ≥70 bpm, MTD for HF meds Comparator: hospitalization rate ivabradine Placebo increased with the treatment effect of Exclusion criteria: comorbidity load heart rate N/A (p<0.0001) with most reduction in stable events in pts with >3 HF. comorbidities for both drug and placebo. Study type: Post hoc analysis of • Hospitalization rate lower RCT for comorbidity loads of ivabradine Size: 6,505 SHIFT Aim: To assess the Inclusion criteria: Over 18 y Intervention: 1° endpoint: • Composite of CV death or hospital admission for Swedberg K et al. effect of heart rate of age, in sinus rhythm, Ivabradine • Composite of CV death or worsening HF among those receiving at least 50% of 2010 reduction by the resting heart rate of ≥70 hospital admission for target beta blocker dose at time of randomization. All (12) selective sinus- bpm, stable symptomatic Comparator: worsening HF cause death; any CV death; HF hospitalization; all- 20801500 node inhibitor chronic HF (NYHA class II- Placebo cause hospitalization; any CV hospitalization; death ivabradine on IV) for ≥4 wk, previous • Primary endpoint: from HF; composite of CV death HF hospitalization, Ivabradine and outcomes in HF admission to the hospital for ivabradine better. Event nonfatal MI. outcomes in HF within 12 mo, LVEF rate 24% vs. 29%. HR 0.82 chronic HF Study type: ≤35% (0.75–0.90); p<0.0001 • No difference in all-cause mortality or CV mortality (SHIFT) randomized, 7 © 2016 American College of Cardiology Foundation and American Heart Association, Inc.

double-blind Exclusion criteria: HF due to placebo-controlled congenital heart disease or • Hospitalization for • Ivabradine better for all-cause hospitalization, HF trial. 1° severe valvular disease. worsening HF: ivabradine hospitalization, CV hospitalization, and composite 2° 677 centers MI within 2 mo, ventricular better. 16% vs 21%, HR: endpoint 37 countries or AV pacing for ≥40% of 0.74 (95% CI: 0.66–0.83; the d, AF or flutter, p<0.001) • Analyzed as time to first event. Size: symptomatic hypotension Median follow-up of 22.9 mo 6,558 • Death from HF: ivabradine 6,505 analyzed The following treatments not better. 3% vs. 5%; HF: • In subgroup analysis, effect limited to those with allowed during study: 0.74 (0.58–0.94); p=0.014 higher baseline heart rate (≥77 bpm) 3,241 ivabradine • diltiazem and verapamil 3,264 placebo (nondihydropyridine CCB) • Use of devices was low (CRT in 1% and ICD in 4%) • class I antiarrhythmics • strong inhibitors of CYP450 • Mean age 61 y 3A4 • When added to GDEM, including beta blocker at optimal dose, ivabradine reduced adverse events, driven largely by HF mortality or HF hospitalization

Adverse Effects: • 1% withdrew due to bradycardia (p<0.001) • Phosphenes 3% (p<0.001)

• Comparable across age groups • AF - ivabradine 9% vs. placebo 8% (p=0.012) SIGNIFY Aim: Assess the Inclusion criteria: Intervention: 1° endpoint: • Adverse Events: Increased bradycardia, AF, Fox et al. 2014 mortality-morbidity Stable CAD without clinical Ivabradine (n=9,550) • Composite of CV death phosphenes and cardiac disorders. (13) benefits of HF and heart rate of ≥70 and nonfatal MI 25176136 Ivabradine in pts bpm and in sinus rhythm, Comparator: • Results: No significant • Significant interaction between ivabradine and with stable CAD persistence and Placebo (n=9,552) difference in incidence of presence of angina in a subgroup analysis (p=0.02). without clinical HF confirmation of ≥1 CV risk 1° endpoint (HR: 1.08; factors 95% CI: 0.96–1.20; Study type: RCT p=0.20), death from CV Exclusion criteria: Serum causes (HR: 1.10; 95% CI: Size: creatinine >200 mcmol /L, 0.94–1.28; p=0.25), 19,102 significant anemia, ALT or nonfatal MI (HR: 1.04; 95% AST >3 times upper normal CI: 0.90–1.21; p=0.60) and value, unstable CV rate of death (HR: 1.06; condition, LVEF ≤40%; MI, 95% CI: 0.94–1.21; coronary revascularization, p=0.35) stroke <3 mo. 1° Safety endpoint:

• Incidence of bradycardia higher in Ivabradine group (p=0.001) BEAUTIFUL Aim: Assess the Inclusion criteria: Intervention: 1° endpoint: 2° endpoints: Fox et al. 2008 mortality-morbidity • Pts ≥55 y of age with stable Ivabradine • Composite of CV death, 1) All-cause mortality (14) benefits of CAD defined as: previous n=5,479 admission for MI and 2) Cardiac death (death from MI or HF or related to a 18757088 Ivabradine in pts MI, previous admission for HF cardiac procedure) with CAD and LV revascularization (PCI or Comparator: 3) CV death (death from a vascular procedure, systolic surgery), or angiographic • Placebo in addition • No difference in composite presumed arrhythmic death, stroke death, other dysfunction evidence of ≥1 stenosis of to appropriate CV 1° endpoint (22.5% vs. vascular death or sudden death of unknown cause) or ≤50%) AND LVEF <40% medication 22.8%; HR: 1.00; 0.91–1.1; admission for HF, Study type: and end diastolic internal n=5,438 p=0.94) 4) Composite of admission for fatal and nonfatal MI or Randomized, dimension of >56 mm. Sinus UA double-blind, rhythm with resting heart • No differences in any 5) Coronary revascularization placebo-controlled rate of ≥60 bpm. prespecified subgroup. 6) CV death • Angina and HF symptoms 7) Admission for HF stable for 3 mo 8) Admission for MI Size: 10,917 • Appropriate conventional CV medication for 1 mo. • No differences in 2° endpoints in overall population. 5,479 ivabradine 5438 placebo Exclusion criteria: MI or • In subgroup with heart rate of ≥70, ivabradine coronary revascularization reduced within the previous 6 mo; 1) admission for AMI (fatal and nonfatal) (HR 0.64; stroke or TIA within 3 mo, 0.49–0.84; p=0.001) PPM or ICD, valvular 2) composite of admission for AMI or UA (HR 0.78; disease likely to need 0.62–0.97; p=0.023) surgery within 3 y, SSS, 3) coronary revascularization (HR 0.7; 0.52–0.93; sinoatrial block, congenital p=0.16) long QT, complete AV block, severe or uncontrolled • 28% in Ivabradine group discontinued medication hypertension, NYHA class (vs. 16%), largely due to bradycardia (13% vs. 2%) IV HF • No difference in significant adverse effects (23% vs. 23%; p=0.70) 1° indicates primary; 2°, secondary; AV, atrioventricular; AF, atrial fibrillation; AST, aspartate transaminase; ALT, alanine aminotransaminase; AMI; acute myocardial infarction; CAD, coronary artery disease; CI, confidence interval; CRT, cardiac resynchronization therapy; CV, cardiovascular; CCB, calcium channel blocker; BEAUTIFUL, Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Disease and Left-Ventricular Dysfunction; bpm, beats per minute; GDEM, guideline-directed evaluation and management; HF, heart failure; HR, hazard ratio; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MTD, maximal tolerated dose; N/A, not available; NYHA, New York Heart Association; pts, patients; PCI, percutaneous coronary intervention; PPM, permanent pacemaker; RCT, randomized controlled trial; SIGNIFY, Study Assessing the Morbidity–Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease; SHIFT, Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial; SSS, sick sinus syndrome; TIA, transient ischemic attack; and UA, unstable angina. Search Terms and Date: studies identified by chairs in December 2015, one study added by Jan 2016.

2013 HF Guideline Data Supplement 18. ACE Inhibitors (Section 7.3.2.2) Study Name, Aim of Study Study Type Background Study Size Etiology Patient Population Endpoints Mortality Trial Duration Absolute Benefit P Values & 95% CI: Author, Year Therapy (Years)

Pretrial standard N (Total) Ischemic/ Inclusion Criteria Exclusion Criteria Primary Secondary Endpoint 1st Year Mortality treatment NonIschemic Endpoint n (Experimental) n (Control)

CONSENSUS To Evaluate influence RCT Diuretics 253; 127;126 CAD 73% Severe APE; Mortality Change in NYHA-FC, 52% placebo group and 0.51 y N/A Crude mortality at end of 6 mo of enalapril on (spironolactone HF/symptoms at hemodynamically LV size, Cr level 36% enalapril group (6 (primary endpoint), 26% in 1987 prognosis of NYHA 53%, mean dose rest/NYHA class import aortic/MV mo mortality: 26% in enalapril group and 44% in placebo class lV HF 80mg), digitalis lV; stenosis; enalpril group and 44% in group—40% reduction (p =0.002). 2883575 (15) (93%), other Increased heart MI w/in prior 2 mo placebo group) Mortality was reduced by 31% at 1 vasodilators, size >600 mL; Unstable angina; y (p=0.001) except ACEI (ie, planned cardiac nitrates 46%) BP: 120/75; HR: surgery; right HF b/c 80; AF 50% of pulm disease; Cr >300 mmol/L

10 y FU of Report on the 10-y open- All pts were offered 315; 77; 58 253 randomized Mortality 10 y 5 pts, all in the enalapril group, CONSENSUS survival at the 10-y label follow- open-label pts included in were long-term survivors 1999 follow up of the pts up study (via enalapril therapy analysis of time (p=0.004). Averaged over the trial randomized in completion of from randomization (double-blind plus open-label 10099910 CONSENSUS. (1st a to death; extension) risk reduction was 30% (16) study to show questionnaire) Survivors (135) of (p=0.008), 95% CI: 11% - 46%. prognostic on the the double-blind improvement by an survival status period included in At end of double-blind study ACEI. Pts in NYHA of pts in analysis of the period, mortality considerably class IV HF treated CONSENSUS time from end of higher among pts not receiving with enalapril or -a RCT. double-blind period open ACEI therapy placebo. After study to death; completion all pts were offered open- Severe, NYHA lV label enalapril therapy).

SOLVD 1991 Study the effect of RCT Diuretics + Digoxin 2569; 1285; 1284 Ischemic LVEF <35%; Mild Age >80 y; Mortality Hospitalizations; 15.70% 3.45 y Treating 1000 Reduced mortality by 16%; (95% enalapril on mortality heart disease to severe Unstable angina; MI Incidence of MI; SOLVD+ pts with CI, 5-26%; p=0.0036) 2057034 (17) and hospitalization in 72% (11% class l/<2% w/in past mo; Cr>2.0 Mortality by specific enalapril for ~3 y pts with chronic HF class lV); mg/dL causes; would save ~50 and EF <35% Combined mortality premature deaths LVEF 25%; BP: and morbidity from and 350 125/77; HR: 80; both SOLVD+/SOLVD- hospitalizations. AF: 8-12%

SOLVD 1992 Study effect of ACEIs RCT No drug treatment 4228; 2111; 2117 History of EF <35%; As per SOLVD+ Mortality; Incidence of HF and 3.12 y Reduced mortality: p=0.30; 95% on total mortality and for HF ischemic Asymptomatic; Combined rate of hospitalization CI: -8-21% 1463530 (18) mortality from CV heart disease mortality and for HF causes, the 85% NYHA class I the incidence

development of HF, (67%) + ll; of HF and and hospitalization rate of EF: 28%; BP: for HF in pts with EF hospitalization 126/78; HR: 75; <35% for HF AF: 4%

SOLVD F/U 12-y FU of SOLVD to 12 y f/u of N/A 6784; 3391; 3393 N/A Participation in N/A Mortality N/A N/A N/A Enalapril extended In the prevention trial, 50.9% of the 2003 establish if the RCTs SOLVD+ and median survival by enalapril group had died c/w 56.4% mortality reduction [SOLVD+ and SOLVD- 9.4 mo in the of the placebo group (p=0.001). 12788569 with enalapril among SOLVD-] combined trials In the treatment trial, 79.8% of the (19) pts with HF was Asymptomatic to (95% CI: 2.8–16.5, enalapril group had died c/w 80.8% sustained, and severe; p=0.004). of the placebo group (p=0.01). whether a NYHA l-lV Combined prevention and subsequent reduction treatment trials: HR for death was in mortality would 0.90 for the enalapril group c/w emerge among those placebo group (95% CI: 0.84–0.95, with asymptomatic p=0.0003). ventricular dysfunction.

ATLAS To compare the RCT N/A 3164; CAD 65% LVEF <=30%; Acute coronary Mortality from Combined risk of all- 5 y High-dose group had 8% lower risk efficacy and safety of NYHA class II, III, ischemic event or all causes cause mortality and of all-cause mortality (p=0.128) 1999 low and high doses 1596 to the low- or IV, despite revascularization hospitalization for any and 10% lower risk of CV mortality 10587334 of ACEI on the risk of dose strategy and treatment with procedure within 2 reason; (p=0.073) than low-dose group. (20) death and 1568 to the high- diuretics for ≥2 mo mo; History of CV mortality, CV Death or hospitalization for any hospitalization in dose strategy. (Treatment for HF sustained or hospitalizations; reason, high-dose group had 12%

chronic HF. than the in ED or hospital symptomatic All-cause mortality lower risk than low-dose group,

large doses that have within 6 mo ventricular combined with CV p=0.002. been shown to required for pts in tachycardia; hospitalizations; Total number of hospitalizations: reduce morbidity and class II); Intolerant of ACEIs; CV mortality combined high-dose group 13% fewer mortality in pts with Prior use of SCr >2.5 mg/dL with CV hospitalizations for any reason HF. digitalis, ACEIs, or hospitalizations; (p=0.021), 16% fewer AIM: Investigate if vasodilators Combined risk of fatal hospitalizations for CV reason low doses and high allowed but not and nonfatal MI plus (p=0.05), and 24% fewer doses of ACEIs have mandated; NYHA hospitalization for hospitalizations for HF (p=0.002). similar benefits. ll-lV (mainly class unstable angina ll); LVEF 23%; SBP 126 mmHg; HR 80; NYHA class: lll (few ll and lV)

Post-MI ACEI Use

SAVE, 1992 To test the RCT Beta-blockers 2231; 1115; 1116 Ischemic Alive 3 d after MI; Failure to undergo Mortality from Mortality from CV 3.5 y Mortality from all causes was hypothesis that the 36%; 100% randomization within all causes causes; significantly reduced in the 1386652 (21) long-term Digitalis 26%; LVEF <40%; 16 d after the MI; Mortality combined captopril group (228 deaths, or administration of Nitrates 51% >21 y of age, but Relative with a decrease in the 20%) as c/w the placebo group captopril to survivors contraindication to EF of at least 9 units in (275 deaths, or 25%); the RR: 19% 11 © 2016 American College of Cardiology Foundation and American Heart Association, Inc.

of acute MI who had <80; the use of an ACEIs surviving pts; (95% CI, 3-32%; p=0.019). baseline LV or the need for such CV morbidity RR:21% (95% CI, 5 -35%; dysfunction but did Killip class I — an agent; (development of p=0.014) for death from CV not have overt HF 60% SCr > 2.5 mg/dl severe CHF or the causes, 37% (95% CI, 20-50%; requiring vasodilator (60% of the ps did recurrence of MI); p<0.001) for the development of therapy would reduce not have even Combination of CV severe HF, 22% (95% CI, 4-37%; mortality, lessen transient mortality and p=0.019) for CHF requiring deterioration in pulmonary morbidity; 2 endpoints hospitalization, and 25% (95% CI, cardiac performance, congestion at of severe HF 5-40%; p=0.015) for recurrent MI. and improve clinical baseline/the time (treatment failure): 1st, outcome. of their acute MI; development of overt HF necessitating EF 31%; BP treatment with ACEI 113/70; and 2nd, HR 78; hospitalization to treat CHD.

AIRE 1993 Investigated the RCT 2006; 1014; 992 Aged ≥18 y, with a Use of an ACEI Mortality from 1.3 y Mortality from all causes was effect of therapy with definite acute MI 3- considered to be all causes significantly lower for pts on 8104270 (22) ACEI ramipril, on 10 d before mandatory ramipril compared to pts on survival in pts who randomization; placebo. RR: 27%; 95% Cl: 11-

had shown clinical Clinical evidence 40%; p=0.002. evidence of HF at of HF at any time Prespecified secondary outcomes: any time after an since acute MI risk reduction of 19% for the 1st acute MI. Also, to validated outcome—namely, death, compare the severe/resistant HF, MI, or stroke incidences of (95% CI: 5% - 31%; p=0.008). progression to severe or resistant HF, nonfatal reinfarction and stroke between the 2 groups.

TRACE 1995 To determine RCT Beta blocker 16%; 1749; 876; 873 Ischemic Consecutive pts Contraindication to Death from Death from a CV The mortality from all 24 lives were saved During the study period, 304 pts in whether pts who LV Calcium antagonist 100% >18 y hospitalized ACEI or a definite any cause cause, sudden death; causes at 1 y was 24%. after 1 mo of the trandolapril group died (34.7%), 7477219 (23) dysfunction soon 28%; Diuretic with MI; Criteria for need for them; Progression to severe treating 1,000 pts as did 369 in the placebo group after MI benefit from 66%; Nitrates MI: chest pain or Severe, uncontrolled HF (hospital admission (42.3%). RR: 0.78 (95% CI, 0.67 -

long-term oral ACE 53%; Digoxin electrocardiographi DM; for HF, death due to 0.91; p=0.001). inhibition. 28%. c changes, progressive HF, or HF In every subgroup, treatment with accompanied by Hyponatremia (<125 necessitating open- trandolapril was associated with a >2X increase in ≥1 mmol/L); label ACEI); reduction in risk. cardiac enzymes; Elevated SCr level Recurrent infarction LV dysfunction (EF (2.3 mg/dL) (fatal or nonfatal); <35%); Change in the wall- motion index (EF) NYHA class 1 - 41%; BP 121/76; HR 81

ACEI indicates angiotensin-converting-enzyme inhibitor; AF, atrial fibrillation; AIRE, Acute Infarction Ramipril Efficacy; APE, acute pulmonary embolism; ATLAS, Assessment of Treatment with Lisinopril and Survival; BP, blood pressure; CAD, coronary artery disease; CHD, chronic heart disease; CHF, congestive heart failure; CONSENSUS Cooperative North Scandinavian Enalapril Survival Study; Cr, creatinine; CV, cardiovascular; C/W, compared with; DM, diabetes mellitus; ED, emergency department; FU, follow-up; HF, heart.

2013 HF Guideline Data Supplement 19. ARBs (Section 7.3.2.3) Study Name, Trial Author, Study Background Duration Year Aim of Study Type Therapy Study Size Etiology Patient Population Severity Endpoints Mortality (Y) Statistical Results N (Total) Pre-trial n standard (Experimental) Ischemic/ treatment. n (Control) Non-Ischemic Inclusion Criteria Exclusion Criteria Primary Endpoint Secondary Endpoint 1st Y Mortality CHARM Discover RCT Diuretics, 2028; 1013; Ischemic 67- Symptomatic HF, EF NYHA ll-lV; mild to Composite of CV CV death, hospital 2.8 y Absolute reduction of 7 major events per 100 Alternativ whether ARB Beta-blockers 1015 70% <40%, no ACEI (b/c of severe (<4% class death or hospital admission for CHF or pts threated - NNT 14 pts to prevent 1 CV e; could improve (55%), intolerance) lV); EF: 30%; BP: admission for CHF nonfatal MI; CV death, CHF death or hospitalization. Granger outcome in spironolacton 130/70; HR: 74-75; admission, nonfatal MI, HR: 0.77 (95% CI: 0.67-0.89); p=0.0004 et al; pts not taking e 24%, AF: 25-26% nonfatal stroke; CV death, (2003) an ACEI Digoxin 45- CHF admission, nonfatal 13678870 (intolerant) 46% MI, nonfatal stroke, (24) coronary revascularization; Death (any cause); New DM CHARM- To investigate RCT Beta blocker- 2548; 1276; Ischemic 62- Symptomatic HF; EF NYHA class ll-lV; Composite of CV CV death, hospital 3.4 y Absolute reduction of 4.4 pts with events per ADDED; if ARB + ACEI 55%; 1272 63% <40%; Treatment with mild to severe (<3% death or hospital admission for CHF or 100 pts treated- NNT of 23 to prevent 1 first McMurray in pts with spironolacton ACEI; Age >18 y class lV); EF 28%; admission for CHF nonfatal MI; CV death, CHF event of CV death or CHF hospitalization. et al; chronic HF e 17%; BP 125/75; HR 74; admission, nonfatal MI, RR: 0.85 (95% CI: 0.75-0.96); p=0.011 (2003) improve Digoxin 58- AF 27% nonfatal stroke; CV death, 13678869 clincal 59% CHF admission, nonfatal (25) outcomes MI, nonfatal stroke, coronary revascularization; Death (any cause); New DM VALIANT; Compare the Randomize Beta- 14,703 Ischemic 100% Age >18 y; Prior intolerance or contra- NYHA l-lV; Death from any 12.5% VAL 2.1 y VAL and CAP: 1.0 (97.5% CI-- 0.90-1.11); Pfeffer et effect of an d double blockers; ASA Valsartan:490 (MI inclusion Acute MI complicated indication to ACEI/ asymptomatic- cause 12.3% VAL--CAP p=0.98 ; al; (2003) ARB, ACEI blind 9 criteria) by HF; LV systolic ARB severe, 13.2% CAP VAL+CAP and CAP: 0.98 (97.5% CI-- 0.89- 14610160 and the multicenter Captopril-: dysfunct (EF <35%), EF 35%; BP: 123/72; 1.09); p=0.73 (26) combination trial 4909 (<40% on radionuclide HR: 76 of the 2on VAL + CAP: ventriculography); mortality 4885 SBP >100 mmHg; Cr <2.5 mg/dL Val-HeFT; Evaluate long RCT Diuretics; 5010; 2511; Ischemic 57% Age >18 y; NYHA ll-lll, lV (only Mortality; Change in EF; 1.92 y Mortality similar for the 2 treatment groups. Cohn et term effects of Digoxin 67%; 2499 NYHA ll, ll, lV; ~2% class lV); Mild Combined • NYHA class, QoL scores; For the combined endpoint: RR: 0.87; 97.5% al; (2001) adding ARB Beta blocker At least 2 wk of to severe; endpoint of Signs and symptoms of HF CI, 0.77-0.97; p=0.009 11759645 to standard 35%; ACEI background meds EF 27%; BP 123/76; mortality and (27) therapy for 93% including ACEIs; AF 12% morbidity HF EF <40% and LVID >2.9 cm/BSA HEAAL Compared the RCT Diuretic drugs 3846 IHD 64% >18 y; Pregnancy or lactation; known NYHA ll-lV (70% ll); Death or Composite endpoint of 4.7 y Treating pts with 150 mg dose instead of 50 study; effects of (77%), beta losartan 150 NYHA class II–IV; LVEF intolerance to ARBs; EF: 33%; BP: admission for HF death or CV admission. median f/u mg dose would result in 1 additional pt w/out Lancet high-dose vs blockers mg (n=1927) <40%, with stable CV Systolic arterial blood 124/77; HR: 71; AF; Additional prespecified the primary event at 4 y for every 31 pts 2009; low-dose (72%), and or 50 mg daily medical therapy for at pressure <90 mm Hg; 28% outcomes included: death, treated. Composite: 828 (43%) pts in 150 mg 374: losartan on ARBs (38%). (n=1919). least 2 wk; Significant stenotic valvular death or all-cause group vs. 889 (46%) in 50 mg group died or 1840-48. clinical Intolerance to ACEI; heart disease; Active admission, CV death, all- admitted for HF (HR: 0.90; 95% CI: 0.82-0.99; 19922995 outcomes in Investigators myocarditis; active cause admission, CV p=0.027) (28) pts with HF. encouraged to start pericarditis; Planned heart admission, admission for • Components: 635 pts in 150 mg group vs. beta blocker and titrate transplantation w/in 6 mo; HF, and changes in the 665 in 50 mg group died (HR: 0.94, 95% CI: to a maximum, coronary angioplasty, CABG, severity of heart disease 0.84-1.04; p=0.24), and 450 vs. 503 pts whenever possible acute MI, UA pectoris, admitted for HF (0.87, 0.76–0.98; p=0.025) cerebrovascular accident, or TIA within the previous 12 wk; Suspected significant renal 13 © 2016 American College of Cardiology Foundation and American Heart Association, Inc.

artery stenosis

CHARM- Aimed to find RCT- Diuretics 83% 7601 pts >18 y; SCr > 265 mcmol /L, serum NYHA ll-lV The primary The annual CV 3.1 y 886 (23%) pts in candesartan and 945 (25%) Overall out whether parallel, Beta blockers (7599 with NYHA class II–IV for at potassium >5.5 mmol/L NYHA ll-lV outcome of the death rate among in placebo group died (unadjusted HR: 0.91; 13678868 the use of an randomized 55% data) least 4 wk; Bilateral renal artery stenosis; Only 3% class lV overall program: the placebo group 95% Cl: 0.83–1.00; p=0.055; covariate aHR: (29) ARB could , double- ACEI 43% 3803 3 distinct populations: symptomatic hypotension all-cause mortality; who had reduced 0.90 95% CU: 0.82–0.99; p=0.032) reduce blind, Spironolacton 3796 pts with LVEF <40% Women of childbearing For all the LVEF was around • Fewer CV deaths (691 [18%] vs 769 [20%], mortality and e 17% who were not receiving potential not using adequate component trials: 9% and was only unadjusted HR: 0.88; 95% Cl: 0.79–0.97; morbidity. Digoxin 43% ACEIs (previous contraception; Critical aortic CV death or 4% in the placebo p=0.012; covariate aHR: 0.87; 95% Cl: 0.78– intolerance) or who or mitral stenosis; MI, stroke, hospital admission group of CHARM- 0.96; p=0.006) were currently receiving or open-heart surgery in the for CHF. Preserved. • Hospital admissions for CHF (757 [20%] vs ACE, and pts with LVEF previous 4 wk; Use of an ARB 918 [24%], p<0.0001) >40% in the previous 2 wk ACEI indicates angiotensin-converting-enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blockers; ASA, aspirin; BP, blood pressure; BSA, body surface area; CABG, coronary artery bypass graft; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; CHD, chronic heart disease; CHF, congestive heart failure; Cr, creatinine; CV, cardiovascular; DM, diabetes mellitus; EF, ejection fraction; FU, follow-up; HEAAL study, effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure; HF, heart failure; HR, heart rate; IHD, ischemic heart disease; LV, left ventricular; LVD, left ventricular dilatation; MI, myocardial infarction; MV, mitral valve; N/A, not applicable; NNT, number needed to treat; NYHA, New York Heart Association; QoL, quality of life; pts, patients; SBP, systolic blood pressure; RCT, randomized control trial; SCr, serum creatinine; TIA, transient ischemic attack; UA, unstable angina; Val-HeFT, Valsartan Heart Failure Trial; and VALIANT, Valsartan in Acute Myocardial Infarction.

2013 HF Guideline Data Supplement 20. Beta Blockers (Section 7.3.2.4)

Study Name, Background Trial Author, Year Aim of Study Study Type Therapy Study Size Etiology Patient Population Severity Endpoints Mortality Duration Statistical Results N (Total) n (Experimental) Inclusion Primary n (Control) Criteria Exclusion Criteria Endpoint Secondary Endpoint Annualized Mortality 1st Y Mortality CIBIS ll CIBIS Investigate the RCT- Diuretics + 2647; 1327; Documented NYHA class lll or Uncontrolled HTN; Moderate to severe. All-cause All-cause hospital 13.2% Placebo group N/A 1.3 y HR: 0.66 (95% CI: ll investigators efficacy of bisoprolol multicenter ACEI; 1320 Ischemic lV MI/UA w/in previous 3 mo; Mean BP: 130/80; mortality admissions 8.8% Treatm't group 0.54-0.81); p<0.0001 and committee in decreasing all- double-blind [amiodarone 50% EF: <35% PTCA/CABG w/in Mean HR: 80; Mean All CV deaths members cause mortality in randiomised allowed--14- 18-80 y old previous 6 mo; EF: 28%; Mean Combined endpoints (1999) chronic HF placebo l6%] AV-block >1st degree w/o LVEDD: 6.7 cm; AF: Permanent treatment 10023943 (30) controlled PPM; 20% withdrawal trial (Europe) Heart rate < 60bpm; resting SBP <100mmHg; renal failure; Reversible obstruct lung disease; Use of beta blocker MERIT-HF; Investigate whether RCT-- Diuretics + 3991; 1991; Ischemic NYHA ll-lV; MI/UA w/in 28 d; Mild to severe. Mean All-cause N/A 11.0% Placebo group N/A 1 y Treatment of 27 pt for MERIT study Metoprolol CR/XL multicenter ACEI 2001 65% 40-80 y old; Contra-indication or BP: 130/78; Mean mortality 7.2% Treatm't group 1 y can prevent 1 Group; (1999) lowered mortality in double-blind [Amiodarone LVEF <40% (36- current use of beta HR: 78; Mean EF All-cause death. 10376614 pts with decreased randiomised NOT allowed] 40 if 6-min walk blocker; 28%; AF 16-17% mortality in 0.66 (95% CI: 0.53- (31) EF and symptoms placebo <450m); PTCA/CABG w/in 4 mo combination with 0.81); p=0.00009 of HF controlled heart rate >68 Planned transplant or ICD; all-cause trial (Europe bpm Heart block >1st degree admission to + USA) w/o PPM; SBP hospital <100mmHg

COPERNICUS Investigate whether RCT--double Diuretics (PO 2289; 1156; Ischemic Euvolumic NYHA Pt requiring hospitalized Severe All-cause Combined risk of death or 19.7% placebo 18.5% in 10.4 mo Treating 1000 pt for 1 ; Packer et al; Carvadiolo is blind or IV) + ACEI 1133 67% class lV; intensive care; Mean BP: 123/76; mortality hospitalization-any reason; [24.0% in pts with placebo group y led to savings of 70 (2002) beneficial in severe (or ARB); LVEF <25%; Use of positive inotropes Mean HR: 83; Mean Combined risk of death or recent or recurrent 11.4% in premature deaths 12390947 HF [Amiodarone No positive or IV; vasodilators w/in 4- EF 20%; hospitalization--CV reason; cardiac Carvedilol group p=0.0014 (32) allowed 17- inotropes or d; Combined risk of death or decompensations] 18%] vasodilators w/in Coronary hospitalization--HF reason; 4 d revascularization/MI/CVA/ Pt global assessment sign VT or VF w/in 2 mo; SBP < 85 mmHg, Heart rate <68, Cr >2.8 mg/dL SENIORS; Assess effects of RCT Diuretics + 2128; 1067; Prior h/o Age >70 New HF therapy w/in 6 wk Mild to severe Composite of All-cause mortality N/A N/A 1.75 y Absolute risk reduction Flather et al; the beta blocker ACEI 1061 CAD in 69% CHF with 1 of the or change in drug therapy Mean BP: 139/81; all-cause Composite of all-cause 4.2%; 24 pts would (2005) Nebivolol in pts >70 (+aldosterone following: w/in 2 wk Mean HR: 79; Mean mortality or CV mortality or all-cause need to be treated for 15642700 y regardless of EF. antagonist in hospitalization Contraindication to beta EF 36% (1/3 with EF hospital hospital admissions 21 mo to avoid one (33) 29%) with CHF w/in a blockers, current use of >35%); admission All cause hospital event year or EF <35% beta blockers admissions RR: 0.86; 95% CI: w/in the past 6 Significant renal CV hospital admissions 0.74-0.99; p=0.039 mo dysfunction CV mortality CVA w/in 3 mo. Composite of CV mortality or CV hospital admissions NYHA class assessment; 6 MWT A Trial of the Designed to RCT ACEIs (if 2708; 1354; Ischemic NYHA class III or Reversible cause of HF NYHA lll or lV (92% Death from any Death from CV causes For pt in NYHA N/A ~2 y 449 pt in placebo Beta-Blocker determine whether tolerated) 1354 59% IV HF present class lll) cause (death due to pump failure functional class III, the group (33%) died, 411 Bucindolol in Pt bucindolol [91% ACE; LVEF <35% Candidates for heart EF 23%; or an ischemic event or annual mortality rate in the bucindolol group with Advanced hydrochloride, a 7% ARB], for >18 y transplantation HR 82; BP sudden death) was 16% in the (30%; HR: 0.90; 95% Chronic HF nonselective beta- at least 1 mo. Cardiac revascularization 117/71; Hospitalization for any placebo group; For pt CI, 0.78-1.02; The Beta- adrenergic blocker Before the procedure within the AF 12% reason with NYHA class IV, unadjusted p=0.10; Blocker and mild publication of previous 60 d Hospitalization because of the annual mortality adjusted p=0.13) Evaluation of vasodilator, would the results of UA HF rate in the placebo Survival Trial reduce the rate of the DIG trial, Heart rate <50 bpm, SBP Composite of death or heart group was 28% Investigators death from any 12 digoxin <80mmHg transplantation Overall: annual 11386264 cause among pt therapies Decompensated HF. LVEF at 3 and 12 mo mortality of 17% in (34) with advanced HF were MI; QoL; and any change in placebo group c/w and to assess its required, but the need for concomitant 15% in the bucindolol effect in various thereafter its therapy group. subgroups defined use became by ethnic discretionary background and [DIG 94%]. demographic criteria — specifically women and members of minority groups. COMET; To compare the RCT Diuretics, 3029; N/A NYHA class ll-lV N/A Mild to severe All-cause N/A N/A N/A 4.8 y All-cause mortality Poole-Wilson effects of carvedilol ACEIs 1511 carvedilol; EF <35% mortality 34% carvedilol and et al; (2003) and metoprolol on 1518 metoprolol Previous CV Composite 40% metoprolol (HR: 12853193 clinical outcome in tartrate admission endpoint of all- 0.83; 95% CI 0.74- (35) pts with HF cause mortality, 0.93; p=0.0017) or all-cause admission

(CIBIS) III; Sufficient data do Multicenter, Diuretics 1010 CAD 62% >65 y, NYHA Treatment with an ACEI, NYHA ll or lll; mild to The primary Combined endpoint at the N/A N/A Mean of In the ITT sample, 178 2005 not currently exist to prospective, 84%; Digoxin Bisoprolol 505; class II or III, and an ARB, or a beta blocker moderate CHF endpoint was end of the monotherapy 1.22±0.42 pt (35.2%) with a 16143696 establish the randomized, 32% Enalapril 505 LVEF <35% (By for >7 d during the 3 mo LVEF 29%; time-to-the-first- phase and the individual y primary endpoint in the (36) optimum order of open-label, echo within the 3 before randomization Heart rate 79; event of components of the primary (maximum bisoprolol-1st group, initiating chronic HF blinded mo) Heart rate at rest <60 bpm SBP 134 combined all- endpoint, at study end and of 2.10 y). and 186 (36.8%) in the therapy (ACEI vs. endpoint Clinically stable without a functioning cause mortality at the end of the enalapril-1st group beta blocker). This evaluation HF (without pacemaker or all-cause monotherapy phase. (absolute difference - was the objective of (PROBE) clinically relevant Supine SBP <100 mm Hg hospitalization CV death 1.6%; 95% CI: -7.6 to the CIBIS III trial-- it trial,24 with fluid retention or at rest CV hospitalization 4.4%; HR: 0.94; 95% compared the effect 2 parallel diuretic SCr≥220 mmol/L CI: 0.77–1.16; on mortality and groups. adjustment within AV block>1° without a noninferiority for hospitalization of 7 d) functioning pacemaker bisoprolol-first versus initial monotherapy Obstructive lung disease enalapril-1st treatment, with either contraindicating bisoprolol p=0.019) bisoprolol or treatment enalapril for 6 mo, followed by their combination for 6 to 24 mo.

ACEI indicates angiotensin-converting-enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; AV, atrioventricular; BP, blood pressure; CABG, coronary artery bypass graft; CHF, congestive heart failure; CIBIS II, Cardiac Insufficiency Bisoprolol Study II; COMET, Carvedilol Or Metoprolol European Trial; COPERNICUS, carvedilol prospective randomized cumulative survival; Cr, creatinine; CR/XL, controlled release/extended release; CV, cardiovascular; CVA, cerebrovascular accident; c/w, compared with; DIG, Digitalis Investigation Group; EF, ejection fraction; HF, heart failure; h/o, history of; HR, hazard ratio; ICD, ICD, implantable cardioverter defibrillator; ITT, intent to treat; MERIT-HF, Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure; MI, myocardial infarction; MWT, minute walk test; NYHA, New York Heart Association; PPM, permanent pacemaker; PTCA, percutaneous transluminal coronary angioplasty; Pts, patients; QoL, quality of life; RCT, randomized control trial; RR, relative risk; SBP, systolic blood pressure; SCr, serum creatinine; UA, unstable angina; USA, United States of America; VF, ventricular fibrillation; VT, ventricular tachycardia; and w/o, without.

References

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